An association between schizophrenic disorders and phenylketonuria (PKU) and heterozygosity for PKU has long been suggested. Since the discovery of PKU in 1934, schizophrenia and other psychotic illnesses have been frequently reported in affected individuals and in their relatives. More recently, schizotypal behavior and other abnormal behaviors have been reported in treated phenylketonurics. To test the hypothesis that PKU heterozygosity is a risk factor for schizophrenia, a study is proposed in which the proportion of PKU heterozygotes in a group of 300 schizophrenic patients will be compared with a group of 600 unaffected individuals (about 2% of normal individuals should be heterozygotes). A study of this size should allow detection of a three-fold increase in the heterozygosity rate among those with schizophrenia. Schizophrenic cases will be so designated based on the administration of a structured clinical interview and on an extensive review of medical and psychiatric records from a variety of sources. All definite cases and all normal subjects will be asked to donate approximately 15 milliliters of blood and to complete a brief questionnaire regarding ethnic background, socioeconomic status, family history of mental illness, the name of a family member for future contact, and other pedigree data (cases only). With DNA extracted from this blood, an accurate determination of PKU heterozygosity status will be made through the use of oligonucleotide probes for normal and mutant alleles of the phenylalanine hydroxylase gene. This is now possible because of the recent discovery that only four or five mutations account for over 90% of PKU alleles. Two of the causative mutations have been elucidated, and data on the remaining mutations should be available within the next several months. While the above hypothesis is the major focus of this proposal, the availability o DNA from a large numb-er of patients and normal subjects will greatly facilitate the testing, through the use of molecular genetic techniques, of other genes that possibly predispose to schizophrenia. In addition, if a family-based linkage study delineates predisposing polymorphism or mutation, the generality of the finding can be rapidly estimated by analyzing our sample of schizophrenics. Finally, pedigree data collected from the cases can be used to identify large families with multiple affected members; such families will be useful for the future generation of a family-based DNA bank which would complement the,cross-sectional bank generated by this project